Open AccessR328 October 2004 Vol 8 No 5 Research Erythropoietin and renin as biological markers in critically ill patients Fabienne Tamion1, Véronique Le Cam-Duchez2, Jean-François Mena
Trang 1Open Access
R328
October 2004 Vol 8 No 5
Research
Erythropoietin and renin as biological markers in critically ill
patients
Fabienne Tamion1, Véronique Le Cam-Duchez2, Jean-François Menard3, Christophe Girault1,
Antoine Coquerel4 and Guy Bonmarchand5
1 Intensive Care Consultant, Medical Intensive Care Unit, Rouen University Hospital, Rouen, France
2 Hematologist, Radioanalysis Laboratory and Hematology Laboratory, Rouen University Hospital, Rouen, France
3 Department of Biostatistics, Caen University Hospital, Caen, France
4 Head of Pharmacology, Radioanalysis Laboratory, Rouen University Hospital, Rouen, and Department of Pharmacology, Caen University Hospital,
Caen, France
5 Head of Medical Intensive Care, Medical Intensive Care Unit, Rouen University Hospital, Rouen, France
Corresponding author: Fabienne Tamion, fabienne.tamion@chu-rouen.fr
Abstract
Introduction During sepsis the endocrine, immune and nervous systems elaborate a multitude of
biological responses Little is known regarding the mechanisms responsible for the final circulating
erythropoietin (EPO) and renin levels in septic shock The aim of the present study was to assess the
role of EPO and renin as biological markers in patients with septic shock
Methods A total of 44 critically ill patients with septic shock were evaluated.
Results Nonsurvivors had significantly higher serum EPO levels than did survivors on admission
(median [minimum–maximum]; 61 [10–602] versus 20 [5–369]) A negative relationship between
serum EPO and blood haemoglobin concentrations was observed in the survivor group (r = -0.61; P
< 0.001) In contrast, in the nonsurvivors the serum EPO concentration was independent of the blood
haemoglobin concentration Furthermore, we observed significant relationships between EPO
concentration and lactate (r = 0.5; P < 0.001), arterial oxygen tension/fractional inspired oxygen ratio
(r = -0.41; P < 0.005), arterial pH (r = -0.58; P < 0.001) and renin concentration (r = 0.42; P < 0.005).
With regard to renin concentration, significant correlations with lactate (r = 0.52; P < 0.001) and
arterial pH (r = -0.33; P < 0.05) were observed.
Conclusion Our findings show that EPO and renin concentrations increased in patients admitted to
the intensive care unit with septic shock Renin may be a significant mediator of EPO upregulation in
patients with septic shock Further studies regarding the regulation of EPO expression are clearly
warranted
Keywords: biological markers, critically ill patients, erythropoietin, renin, septic shock
Introduction
Sepsis is an excessive systemic response to infection leading
to numerous reactions in the host, including release of
proin-flammatory and anti-inproin-flammatory cytokines [1] During sepsis,
the endocrine, immune and nervous systems produce a
multi-tude of biological responses Further evaluation of their role in
sepsis is warranted because this may yield insights that could help us to improve therapeutic outcomes [2]
Use of steroids as an adjunct in septic shock has been pro-posed [3] Some studies demonstrated adrenal insufficiency
in septic patients with poor survival where supplementary
Received: 19 December 2003
Revisions requested: 13 February 2004
Revisions received: 7 April 2004
Accepted: 5 June 2004
Published: 9 August 2004
Critical Care 2004, 8:R328-R335 (DOI 10.1186/cc2902)
This article is online at: http://ccforum.com/content/8/5/R328
© 2004 Tamion et al.; licensee BioMed Central Ltd This is an Open
Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL
AT1 = angiotensin II receptor subtype 1; EPO = erythropoietin; FiO2 = fractional inspired oxygen; MAP = mean arterial pressure; PaO2 = arterial oxy-gen tension; SAPS = Simplified Acute Physiology Score.
Trang 2steroids were not administered [4,5] Acute-phase protein
(APP) synthesis represent a non-specific response of the liver
and induce the production of similar proteins [6] Of the
acute-phase proteins studied in humans, findings with C-reactive
protein have shown that this protein is a particularly useful
indi-cator of progression of various pathological states [7,8]
Erythropoietin (EPO) is a response element that is related to
hypoxic injury [9] It is also a glycoprotein hormone that is
pri-marily released by the kidney, and which stimulates red blood
cell production in order to increase oxygen transfer and
deliv-ery [10] In vitro and in vivo evidence suggests that hypoxia
and anaemia are the most important stimuli of increased EPO
production [11] Reduced arterial oxygen content associated
with anaemia or hypoxia is the predominant stimulus for EPO
production [12,13] Conditions associated with anaemia
usu-ally result in an exponential increase in EPO synthesis within
minutes to hours [14] The EPO response to known
physiolog-ical stimuli is blunted in critphysiolog-ically ill patients, and so EPO
defi-ciency may contribute to the development of anaemia in these
patients [15] Abnormally high serum EPO levels appear to be
a negative prognostic indicator in patients suffering from
sep-tic shock [16,17] However, little is known regarding the
mechanisms responsible for the final level of circulating EPO
in septic shock
Recently, some authors have emphasized a possible influence
of the renin–angiotensin system on EPO gene expression
[18] Renin is released by the kidney, and its regulatory
mech-anisms include stimulation by postcapillary output in kidney
perfusion and adrenergic stimulation by β-receptors [19,20]
Current evidence suggests that angiotensin II may be involved
in the regulation of renal EPO production [18] The signal
appears to be mediated via angiotensin II receptor subtype 1
(AT1) receptors [21] Thus, angiotensin II may be considered
an important physiological modulator of EPO production in
humans
The aim of the present study was to assess the potential utility
of EPO and renin as biological markers in patients with septic
shock
Methods
Patients
The present study was approved by the Hospital Ethics
Com-mittee and written informed consent was obtained from each
patient's closest relative The study included 50 consecutive
patients with septic shock, as defined by the American
Col-lege of Chest Physicians/Society of Critical Care Medicine
Conference Consensus Committee, over 1 year (November
1999–November 2000) Patient inclusion criteria, after
opti-mal volume resuscitation, were as follows (at baseline): mean
arterial pressure (MAP) below 60 mmHg; signs of altered
per-fusion, such as as oliguria (<30 ml/hour) or increased lactate
level; and a cardiac index greater than 3.5 l/min per m2
All patients were included in the study within 24 hours of meet-ing these criteria Volume resuscitation was considered opti-mal when, at a given level, infusion of additional fluids was no longer accompanied by an increase in cardiac index After optimal volume resuscitation, vasopressor agents were admin-istered according to the therapeutic protocol For noradrena-line (norepinephrine), the dose was started at 0.3 µg/kg per min The infusion rate was titrated with respect to MAP at 5-min intervals to achieve a MAP in excess of 80 mmHg with a stable or increased cardiac index If necessary, after the first hour the vasopressor agent was again titrated to achieve the same MAP Dobutamine was administrated to patients with low cardiac index (<2.5 l/min per m2)
In addition, a diagnosis of sepsis required confirmation of an ongoing infectious process, as indicated by one of the follow-ing criteria: one positive blood culture of a known pathogen; and suspected or evident source of systemic infection, from which a known pathogen was cultured
The Multiple Organ Dysfunction Score was calculated as described by Marshal and coworkers [22] The severity of ill-ness was assessed using the Simplified Acute Physiology Score (SAPS) II within 24 hours after admission to the medical intensive care unit Patients were followed for 28 days after the start of the study or until death
Excluded from the study were patients with a previous medical story of malignant disease (cancer and haematologic malig-nancy), AIDS, chronic renal failure (measured creatinine clear-ance <50 ml/min), chronic hepatic insufficiency, severe chronic obstructive pulmonary disease requiring oxygen ther-apy, refractory anaemia (iron deficiency, aplastic anaemia) or acute anaemia (haemolytic anaemia, pulmonary haemorrhage),
or prior administration of EPO or transfusion To describe spe-cifically the hormonal response elicited by the sepsis process itself, we excluded patients with pre-existing diseases that could be responsible for hormonal dysfunction, particularly in the hypothalamic–hypophyseal–adrenal axis and the renin– angiotensin–aldosterone system Because EPO deficiency may be expected in acute renal failure, as in chronic renal fail-ure, we excluded six patients with acute renal failure
Data and blood sampling and processing
Descriptive data consisting of demographics, diagnosis, clini-cal data, and severity score were recorded Blood samples were collected from patients on admission to the medical intensive care unit Then, blood samples were obtained every
24 hours for the following 48 hours Patients who died were sampled in this sequence until the time of death Except for analyses that were performed immediately (gas pressure, ion-ogram, haemogram), blood samples were collected in
EDTA-containing tubes, centrifuged for 10 min at 1300 g and stored
in multiple aliquots at -70°C Plasma samples were thawed at
Trang 337°C once before use in the assays to obtain results among
specific samples of hormone analysis
Routine laboratory evaluation
Routine laboratory tests were performed at baseline and
included arterial blood gas evaluation, creatinine, bilirubin,
platelets, leucocytes, and the arterial oxygen tension (PaO2)/
fractional inspired oxygen (FiO2) ratio (hypoxaemia score)
For lactate measurements, arterial blood samples were
col-lected in tubes containing fluoride oxalate Lactate was
meas-ured using an enzymatic colorimetric method adapted for an
automatic analyzer (Beckman Instruments, Paris, France) and
2 mmol/l was considered the upper limit of the normal range
Erythropoietin measurement
EPO concentrations were determined using an
immunoenzy-matic assay (R & D Systems, Paris, France) This assay is
highly specific and can detect EPO concentrations as low as
0.25 UI/l The normal range in healthy adults is 5–25 UI/l For
values from 10 to 500 UI/l the assay accuracy was better than
7% and 5% during intra-assay and interassay comparisons,
respectively
Renin measurement
Renin was measured on the basis of its action on angiotensin
in plasma, generating angiotensin I Renin concentrations
were determined by radioimmunoassay (SANOFI Pasteur,
Paris, France) Normal values in healthy adults range between
7 and 19 ng/l
Statistical analysis
Qualitative values were analyzed using Fischer's exact test
Differences between admission values for survivors and
non-survivors were tested for significance using Mann–Whitney
U-test Correlation between two variables was assessed using
the Spearman rank test Differences between variables on day
1 and on subsequent days were evaluated using the Wilcoxon
signed rank test The results of these tests are expressed as
mean ± standard deviation, or as median (range; minimum–
maximum) P < 0.05 was considered statistically significant.
Results
Baseline characteristics of the patients
In the present study a total of 44 patients were followed up
over 1 year The baseline demographic data for the patients
are shown in Table 1 The mean patient age was 61 ± 10 years
in the survivors and 58 ± 11 in the nonsurvivors The mean
SAPS II score on admission was 52 ± 10.6 in survivors and
56 ± 9.5 in nonsurvivors Thirteen out of 44 patients had died
by day 28, two of them in the second day after admission The
cause of death was sepsis-related multiple organ failure The
sources of infection leading to study admission are also listed
in Table 1 Thirteen patients had hypoxaemia, defined as
par-tial oxygen saturation below 88% After optimal volume
resus-citation, vasopressor agents were administered All patients received noradrenaline or noradrenaline/dobutamine Noradrenaline was administered to 29 patients and noradren-aline/dobutamine was administered to 15 patients at doses shown in Table 1 Anaemia developed in all patients, but there were no significant differences between survivors and nonsur-vivors at admission or after 24 or 48 hours (Table 2) Blood haemoglobin concentrations were 10.5 (9.8–11.2) g/dl and 10.2 (9.3–11.3) g/dl, respectively, in survivors and nonsurvi-vors at admission No patient received a blood transfusion dur-ing the study, and none received steroids durdur-ing this observational study
Predictive value of admission parameters
Admission values for patients were stratified according to whether they survived or died and were compared between groups (Table 3) Comparisons were made to determine whether differences in routine parameters could serve as prognostic indicators When admission values were stratified
in this manner, three variables (arterial pH, PaO2/FiO2 ratio, and serum bilirubin) were significantly different between the two groups
Time course of erythropoietin and renin levels
The time course of EPO and renin values are shown in Table
2, with patients stratified according to survival Nonsurvivors had significantly higher serum EPO levels than did survivors throughout the study (61 [10–602] UI/l versus 20 [5–369] UI/
l on admission) No significant changes in the survivor patients were observed from admission to the end of day 2 (admission
20 [5–369] UI/l, 1 day 15 [1–512] UI/l, 2 days 14 [1–191] UI/ l)
On admission, nonsurvivors exhibited high renin levels How-ever, this difference did not reach statistical significance in comparison with survivors (82 [7–1020] mmol/l in nonsurvi-vors versus 47 [2–1060] mmol/l in survinonsurvi-vors) Survinonsurvi-vors exhib-ited a significant decrease from their initial values on day 1 and day 2, whereas no change was observed in nonsurvivors The
number of patients, particularly nonsurvivors (n = 13), was
lim-ited, and this may limit the ability to detect significant relationships
Correlations between different variables
A negative relationship between serum EPO and blood
hae-moglobin concentrations was observed in the survivors (n = 31; r = -0.61; P < 0.001) In contrast, in nonsurvivors (n = 13)
the serum EPO concentration was independent of the blood haemoglobin concentration (Fig 1)
On admission there was a significant correlation between
EPO and SAPS score (r = 0.6; P < 0.001) However, serum renin concentration was independent of SAPS score (r =
-0.005; not significant) on admission (Table 4) On examining relationships between admission variables and outcome, we
Trang 4found the greatest correlation for EPO concentration
Furthermore, on admission we observed significant
relation-ships between EPO concentration and lactate (r = 0.52; P <
0.001), PaO2/FiO2 ratio (r = -0.41; P < 0.005), arterial pH (r
= -0.58; P < 0.001) and renin concentration (r = 0.42; P <
0.005)
Figure 2 shows the receiver operating characteristic curves for EPO, renin, lactate and arterial pH on admission A cutoff point was determined graphically for each parameter An EPO con-centration of 50 UI/l, a renin concon-centration of 50 ng/l and an arterial pH of 7.35 were the most sensitive and specific cutoff points (EPO: sensitivity 77%, specificity 81%; renin:
sensitiv-Table 1
Demographic data for the study population (n = 44)
Parameter Survivors (n = 31) Nonsurvivors (n = 13) P
Sex (n)
Length of ICU stay (days) 6.1 (4–21) 7.4 (5–23) NS Primary site of infection
Patients on inotropes
Drug titration (µg/kg per min)
Values are expressed as mean ± standard deviation, or as median (range) ICU, intensive care unit; MODS, Multiple Organ Dysfunction Score;
NS, not significant; SAPS, Simplified Acute Physiology Score.
Table 2
Erythropoietin, renin and haemoglobin values in survivors and nonsurvivors at different times: admission, 24 hours and 48 hours
Parameter Admission 24 hours 48 hours
Erythropoietin (UI/l)
Survivors 20 (5–369) 15 (1–512) 14 (1–191)
Nonsurvivors 61 (10–602)* 100 (7–652)* 35 (13–477)*
Renin (mmol/l)
Survivors 47 (2–1060) 21 (2–442) 20 (3–219)
Nonsurvivors 82 (7–1020) 80 (10–706)* 77 (22–410)*
Haemoglobin (g/dl)
Survivors 10.5 (9.8–11.2) 10.4 (10–10.8) 10.2 (9.3–10.8)
Nonsurvivors 10.2 (9.3–11.3) 10 (9–10.5) 10.3 (9.5–10.5)
Values are expressed as median (range) *P < 0.05 versus survivors.
Trang 5ity 70%, specificity 53% [P = 0.20]; lactate: sensitivity 62%,
specificity 68% [P = 0.07]; arterial pH: sensitivity 85%,
spe-cificity 77% [P < 0.001]) This model shows that EPO and
arterial pH on admission predicted outcome optimally (Table
5) On admission, renin and lactate were poor predictors of
prognosis in this model
For renin, we found significant correlations with lactate (r =
0.52; P < 0.001) and arterial pH (r = -0.33; P < 0.005) No
correlation was found between renin concentration and other
biological parameters
Discussion
The results presented here indicate that EPO and renin
con-centrations increased in patients admitted to a medical
inten-sive care unit with septic shock Maximal concentrations of
EPO and renin were also observed in nonsurvivors A
signifi-cant difference was apparent in EPO and renin levels from
admission to day 2 between patients who survived and those
who died Furthermore, EPO levels were significantly
corre-lated with disease severity, as determined using clinical scores
(SAPS II, organ score failure score) EPO in critically ill
patients and its relationship with prognosis have previously
been reported [16,23] Abnormally high serum EPO level
appeared to be a negative prognostic indicator in those
patients We report here, for the first time, a cutoff value of
EPO that separates survivors and nonsurvivors with good
sen-sitivity and specificity Analysis of receiver operating
character-istic curves showed that, under the conditions of the present
study, a cutoff for EPO of 50 UI/l on admission was optimal for
predicting death Our data also suggest that EPO synthesis is
activated to a greater degree in nonsurvivors than in survivors
The data presented here regarding the prognostic value of
EPO confirm and extend findings of similar, limited studies
conducted in critically ill patients, particularly in children [17]
Erythropoiesis is regulated principally through EPO, a
hor-mone glycoprotein that is produced in the renal peritubular
cells, which is responsible for the maturation and proliferation
of the erythroid cell line [24] In vivo, plasma EPO
concentra-tions represent a complex interaction between EPO synthesis and degradation [25] EPO is metabolized in the liver, under-goes renal excretion and is probably catabolized after utiliza-tion in erythropoietic tissues Increased plasma EPO concentrations can be observed within 2 hours of exposure of individuals to acute hypoxic or anaemic conditions [26,27]
Local and circulating substances, including prostaglandin, arachidonic acid, adenosine, glucocorticoids and cytokines, are known to modulate EPO production [27] Cytokines have
been shown to suppress the in vitro synthesis of EPO in
human cell cultures [28,29] Interleukin-6 upregulates EPO expression in a dose-dependent manner, whereas
interleukin-1 and tumour necrosis factor downregulate EPO production [10] Therefore, control of EPO production in sepsis remains unclear These cytokines are thought to play an important role
in blunting the EPO response to anaemia during sepsis
Table 3
Haemodynamic and metabolic variables in the study population on admission
Variable Survivors (n = 31) Nonsurvivors (n = 13) P
Heart rate (beats/min) 115 ± 35 120 ± 41 NS
Leukocyte count (cells × 103/mm3) 14 ± 11 12 ± 4.1 NS
Platelet count (cells × 10 3 /mm 3 ) 167 ± 98 142 ± 86 NS
Serum bilirubin (µmol/l) 22 ± 24 50 ± 35 0.0008
Serum lactate (mmol/l) 4.5 ± 4.4 6.8 ± 4.8 NS
Values are expressed as mean ± standard deviation MAP, mean arterial pressure; NS, not significant; PaO2/FiO2, arterial oxygen tension/
fractional inspired oxygen ratio.
Figure 1
Relationship between haemoglobin and erythropoietin (EPO) concen-trations in survivors (S) and nonsurvivors (NS)
Relationship between haemoglobin and erythropoietin (EPO) concen-trations in survivors (S) and nonsurvivors (NS).
Trang 6[30,31] Our immunoassay data indicate that EPO production
is not lowered in septic shock patients, despite the
inflamma-tory response Several studies have reported that EPO levels
are unexpectedly low in critically ill patients in relation to their
haemoglobin levels, and that could play a role in the
development of anaemia in these patients In the present
study, serum EPO concentrations were independent of blood
haemoglobin concentration in the nonsurvivors In contrast, in
survivors the serum EPO concentration was dependent on
blood haemoglobin concentration The differences between
these studies may be due to the timing of blood samples taken
to determine EPO concentration
We also demonstrated a significant correlation between serum EPO concentration and hypoxia score (PaO2/FiO2 ratio) and lactate values However, these data do not demon-strate a direct causal relationship between EPO concentration and hypoxic injury in septic shock In the absence of anaemia, EPO is increased by tissue hypoxia induced by extreme phys-iological conditions and during septic shock [32] EPO syn-thesis is subject to regulation by tissue hypoxia with negative feedback (EPO has a blood half-life of 5 hours) when the recovery of normal oxygen pressure occurs [33,34] During these extreme conditions, hypoxia also induced stress hor-mone release [35] In sudden infant death, increased EPO
lev-Figure 2
Receiver operating characteristic curves for (a) erythropoietin (EPO), (b) arterial pH, (c) renin and (d) lactate
Receiver operating characteristic curves for (a) erythropoietin (EPO), (b) arterial pH, (c) renin and (d) lactate The cutoff point for each parameter is
specified in the text.
Trang 7els suggested the presence of heavy hypoxic stress before
death [36] Evidence of the involvement of common
mecha-nisms in controlling hypoxia, and of interleukin-6-dependent
induction of the EPO gene and of several acute-phase protein
genes has been reported [37-39] Further studies are required
if we are to understand fully the regulation of EPO expression
by hypoxia and inflammatory mediators during septic shock
Downregulation of adrenergic receptors (AT1 and AT2), which
represents a link between the renin–angiotensin system and
angiotensin II induced adrenal catecholamine secretion, could
be responsible for the lack of endogenous catecholamines
during sepsis [40,41] It is suggested that this downregulation
of angiotensin II receptors is the main reason for the
attenu-ated responsiveness of blood pressure to angiotensin II Our
results demonstrate an increased renin level in all patients and
a significant relationship between EPO and plasma renin
Plasma renin progressively decreased in survivors, but it
remained significantly elevated in the nonsurvivors on day 2 In
a recent report it was suggested that angiotensin II can
increase renal EPO production in humans [42,43] The
influ-ence of the renin–angiotensin system on EPO production can
be blocked by specific AT1 receptor antagonists [21] One
signal for the control of EPO production in humans may be
mediated by angiotensin II (AT1) receptors Thus, angiotensin
II may be considered an important physiological modulator of
EPO production in humans Renin could potentially be respon-sible for the final increase in circulating EPO in nonsurviving patients with septic shock
In sepsis, the endocrine, immune and nervous systems pro-duce a multitude of biological responses High serum EPO and renin levels appeared to be negative prognostic indicators
in these patients The mechanisms responsible for the final increase in circulating EPO in critically ill patients remain unclear According to our findings, renin may be considered an important mediator of EPO upregulation in patients with septic shock Nevertheless, further studies of the regulation and the role played by EPO expression are warranted in patients with septic shock
Competing interests
None declared
Acknowledgements
The authors thank Richard Medeiros, Rouen University Hospital Medical Editor, for his valuable advice in editing the manuscript.
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Table 4
Correlations of related variables with plasma levels of erythropoietin and renin on admission in patients with septic shock
Serum lactate H0 (mmol/l) 0.5 <0.001 0.52 <0.001
Arterial pH -0.58 <0.001 -0.33 <0.05
Leukocyte count (cells × 10 3 /mm 3 ) -0.11 NS -0.003 NS
Platelet count (cells × 10 3 /mm 3 ) -0.13 NS 0.02 NS
Serum bilirubin (µmol/l) 0.08 NS 0.08 NS
EPO, erythropoietin; NS, not significant; PaO2/FiO2, arterial oxygen tension/fractional inspired oxygen ratio.
Table 5
Multivariate predictors of outcome to septic shock
Variable Odds ratio 95% CI P
EPO 11.8 2.7–52 0.0001
Renin 2.4 0.8–9 0.2
Arterial pH 15.95 3–74 0.0001
Lactate 3.2 0.9–11 0.07
CI, confidence interval; EPO, erythropoietin.
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• The mechanisms responsible for the elevated circulat-ing EPO levels in these critically ill patients are unclear
• Renin may be considered an important mediator of EPO upregulation in patients with septic shock
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